The human immunodeficiency virus (HIV) causes the acquired immunodeficiency syndrome (AIDS), which is the deadliest pandemic of the modern world. Despite the availability of several categories of anti-HIV drugs, AIDS remains incurable. This proposal is aimed at revealing the structural mechanisms underlying the function of viral infectivity factor (Vif), an HIV-1 accessory protein essential for viral replication in vivo. The proposed studies will help identify the potential target sites for developing Vif- inhibiting compounds, which might lead to novel anti-HIV drugs. Upon hijacking the Cul5-ElonginB-ElonginC ubiquitin ligase machinery of the host cells, Vif is able to accelerate the ubiquitination of APOBEC3G, which is a cytidine deaminase produced by the human innate immunity system in order to block viral life cycle. By ubiquitinating APOBEC3G, Vif targets the host enzyme to the proteasome and induces its rapid degradation. Since specific interactions with at least three host proteins are required for its function, Vif represents a novel drug target with multiple opportunities for therapeutic interference. In this proposal, we plan to use protein complex X-ray crystallography to reveal the structural basis of Vif's function. Specifically, we propose to determine (1) the ternary complex structure of Vif-ElonginC-ElonginB, (2) the quaternary complex structure of Cul5-Vif-ElonginC-ElonginB, and (3) the structure mechanisms of Vif-APOBEC3G interactions. AIDS, the deadliest pandemic of the modern world, is caused by human immuno- deficiency virus (HIV) infection. Although several categories of anti-HIV drugs are available, none can cure AIDS. This proposal is aimed at studying the structural basis of the functions of a crucial HIV protein in order to help future design of novel anti-HIV drugs. [unreadable] [unreadable] [unreadable]